ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO725

Secreted Frizzled Related Protein 2: A New Therapeutic Target for Glomerular Disease?

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Papakrivopoulou, Eugenia, Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
  • Lindenmeyer, Maja, Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany
  • Mason, William John, Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
  • Long, David A., Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
Background

Wnt/b-catenin signalling,critical during development but silenced in adult kidneys,is re-activated in podocytes following injury and plays a detrimental role in glomerular injury.Secreted frizzled-related proteins (sFRPs) modulate Wnt signalling and are involved in conditions such as myocardial infarction and cancer but their role in glomerular pathology is unknown.Here,we examined the role of sFRP2 in podocyte injury using in vivo and in vitro approaches.

Methods

Glomeruli from patients with minimal change disease,focal and segmental glomerulosclerosis,Type 2 Diabetes Mellitus and healthy donor kidneys were isolated from biopsy specimens and gene expression examined on Affymetrix gene chip arrays. Adriamycin (ADR) nephropathy was induced in Balb/c mice with 10mg/kg IV ADR.sFRP2 neutralising antibody or IgG was injected at day 0, and every 3 days, until day 14.Urine and serum samples were collected at 7 and 14 days.In a separate experiment, mRNA changes were examined in isolated glomeruli 2 days after ADR. An immortalised mouse podocyte cell line was used for in vitro experiments.

Results

sFRP2 mRNA levels were significantly upregulated (6 to 24-fold) versus live donor controls,in all patient cohorts. In mice,ADR injury increased glomerular sFRP2 mRNA expression (2-fold, p<0.05) 48hrs after induction,prior to the appearance of albuminuria and in vitro,ADR induced podocyte sFRP2 mRNA expression (10-fold, p<0.01).Increased sFRP2 staining was observed in podocytes following ADR injury.Exposure of podocytes in vitro to sFRP2 led to longer processes (53± 4.6 vs 76 ± 9.1,arbitrary units,p<0.05) and more processes/cell (8 ± 0.96 vs 11 ± 1.01,p<0.05).Next, we examined the effect of sFRP2 blockade on ADR-induced glomerular injury.ADR significantly increased albuminuria compared to baseline (383.23 vs 0.04mg/24hr, p<0.001,n=10 mice/group) and blood urea nitrogen (BUN) levels (38.14 vs 21.57mg/dL, p<0.05,n=10) at 14 days.sFRP2 inhibition significantly attenuated both albuminuria (40 vs 383 mg/24hr,p<0.05,n= 10) and BUN levels (21.72 vs 38.14mg/dL,n=10,p<0.05) compared to IgG control, at the same time point.No changes in body to kidney weight ratio were observed.

Conclusion

Glomerular sFRP2 expression is upregulated in response to injury.This appears to be detrimental for podocytes as inhibition by antibody blockade attenuates the response to injury.

Funding

  • Government Support – Non-U.S.